Bone Abstracts

In clinical studies, denosumab (DMAb) administration up to 8 years is associated with continued increases in bone mineral density (BMD) and low fracture incidence despite persistently low bone turnover markers and limited iliac crest tetracycline labelling (Papapoulos 2013). We tested the hypothesis that, with persistently low bone remodelling, BMD increases may result from a non-remodelling dependent mechanism to accrue bone matrix. We examined the fluorochrome labelling pattern in proximal femur sections from ovariectomized (OVX) cynomolgus monkeys (cynos) treated with DMAb. Following OVX, mature 9+ years old cynos were treated with vehicle (n=20) or 25 mg/kg DMAb (n=14) monthly for 16 months. Fluorochrome labels were administered at months 6, 12 and 16. As expected from the potent anti-remodelling effect of this regimen (25× clinical DMAb dose), bone resorption and formation indices histologically and by serum markers were very low (Kostenuik 2011). However, DXA femoral neck BMD continued to rise from baseline in the DMAb group: 5.9 and 11.3% at months 6 and 16 respectively. There was little surface label within the trabecular compartment in proximal femur sections in the DMAb group. In contrast, consistent and prominent labelling was observed in the cortex, primarily on both the superior endocortex (12/14 cynos) and the inferior periosteal surface (11/14 cynos). These regions typically contained all three superimposed labels over smooth cement lines, spanning months 6–16, suggesting that modelling-based bone formation was continuous during administration of DMAb. Persistent cortical bone modelling on a background of maximal suppression of remodelling provide a possible explanation for the progressive increases in BMD and mass observed with DMAb treatment at the hip. Importantly, augmentation of bone mass occurred at biomechanically relevant sites of the femur neck, corresponding to significant increases in bone strength (Ominsky 2011). Thus, there is evidence in cynos that continual modelling-based bone formation occurs during DMAb therapy. If applicable to human studies, this could provide an explanation for the increase in cortical thickness and mass observed in clinical trials. This study may provide the first histological evidence of a potential mechanism responsible for clinical observations of continued BMD increases and low fracture rates with long-term DMAb treatment in the FREEDOM Extension.